NORADRENALINE MEDIATES PARADOXICAL EFFECTS ON RAT NEOCORTICAL NEURONSAFTER GABA WITHDRAWAL

1. The aim of the present study was to determine the role of noradrene rgic neurotransmission in neuronal activities intracellularly recorded in neocortical slices obtained from rats presenting the gamma-aminobu tyric acid (GABA) withdrawal syndrome (GWS), a focal epilepsy consecut ive to the interruption of a chronic intracortical GABA infusion into the somatomotor cortex. Neurons recorded in the epileptic focus area ( n = 52) were bursting or nonbursting cells. Intrinsic bursting (IB, n = 20) cells presented bursts of action potentials (APs) to an intracel lular depolarizing current injection and paroxysmal depolarization shi fts (PDSs) to white matter stimulation. Synaptic bursting (SB, n = 22) cells presented only PDSs. Nonbursting (NB, n = 10) cells presented n o burst after either synaptic stimulation or depolarizing current inje ction. Results were compared with those obtained from NB neurons (n = 4) recorded in slices from saline-infused rats. 2. In all of the recor ded neurons, bath application of norepinephrine (NE, 10 and 100 mu M) provoked a depolarization( 1-5 mV) associated with a decrease in input K+ conductance having a mean reversal potential at -90 to -102 mV, no t significantly different for bursting and nonbursting cells. This rev ersal potential differed from that of Cl--mediated inhibitory postsyna ptic potentials (-70 mV) elicited in NB cells by electrical stimulatio n of the white matter. 3. In IB cells, the NE-induced depolarization r eplaced the intrinsic bursts by a sustained repetitive discharge of si ngle APs and caused intrinsic bursts to appear during previously subth reshold depolarizing current pulses. These NE-increased activities wer e abolished by dihydropyridine nitrendipine (1 mu M) and by Cd2+ (0.5 mM) or Co2+ (2 mM), thus confirming that Ca2+ currents contribute to b urst generation in IB cells. 4. In both NB and SB cells recorded in sl ices from GWS rats, NE provoked the appearance of intrinsic bursts of APs during steps of depolarizing current injections. In addition, in N B cells, NE caused synaptic bursts to appear after white matter stimul ation. These NE-induced bursts were dihydropyridine (nitrendipine, 1 m u M)- and Cd2+ (0.5 mM)- or Co2+ (2 mM)-sensitive and were related to an increased AP-afterdepolarization. The fast AP-afterhyperpolarizatio n was not affected by NE. In NB cells recorded in slices from saline-i nfused rats (n = 4) NE did not provoke the appearance of bursts even w hen stimulation intensity was increased up to three times. 5. The afte rhyperpolarization (AHP) that follows either individual PDSs in IB and SB cells, or the bursts induced by injection of a brief depolarizing current step in IB cells, increased by 40-45% during NE application. T his resulted in a decrease in amplitude and duration of PDSs (by 50%) and in an increase of their frequency up to 5 Hz. The equilibrium pote ntials of AHPs in the control situation and during NE were similar and corresponded to the equilibrium potential for K+ ions (-90 mV). The A HPs were not modified by isoproterenol(10 and 100 mu M), a beta-adrene rgic agonist. 6. In conclusion, NE has paradoxical effects on cortical neurons recorded in the epileptic focus area of GWS rats by compariso n to those recorded in normal cortex: it promotes appearance of burst patterns in NB and SB cells, and it accelerates the postburst repolari zation in IB and SB cells. Both effects are probably related to an inc rease of GWS-related Ca2+ currents, although a direct effect on AHP cu rrents cannot be excluded. This hypothesis is supported by recent anat omic data revealing the existence of a local noradrenergic hyperinnerv ation in the epileptic focus zone. In living animals presenting GWS, a release of NE in the area of the epileptic focus may therefore contro l AHPs after spontaneous PDSs and the frequency of the correlative ele ctroencephalographic spikes, and thus determine the transition from is olated spikes to sustained ictal discharges.